PROJECT SUMMARY/ABSTRACT Posttraumatic stress disorder (PTSD) is the 5th most prevalent mental disorder in the USA. The gold-standard treatment for PTSD includes exposure-based therapy, which relies on adequate extinction processes to be successful in reducing symptoms. Although the efficacy of exposure therapy is scientifically established, many patients do not satisfactorily benefit and symptomatic relapse following treatment is common. Therefore, there is a pressing need to identify effective novel options to improve the effectiveness of exposure therapy for PTSD treatment. A laboratory analogue for exposure-based therapy is the extinction of conditioned fear, often designated as ?extinction learning?. The goal of extinction, in the clinic and research laboratory, is to form new safety memories that can be recalled in order to inhibit fear responses associated with the original trauma. The ability to remember new safety memories after extinction is termed ?extinction retention?. Adequate extinction learning and retention is supported by the ventromedial prefrontal cortex (VMPFC), signifying ?top-down? prefrontal regulation of fear expression. Abnormalities in VMPFC functioning and extinction retention are extensively associated with PTSD. Accordingly, our group piloted the use of noninvasive transcranial direct current stimulation (tDCS) to facilitate VMPFC function during extinction in a Pavlovian fear conditioning paradigm. Preliminary results suggests that tDCS could enhance extinction retention, but this effect appears to depend on the timing of stimulation in relation to extinction learning. Specifically, our preliminary evidence suggests tDCS after extinction learning might have stronger effects on extinction retention versus stimulation during extinction learning. An essential next step is to determine the effect of timing of VMPFC-targeted tDCS, and thus whether tDCS during or immediately following extinction learning more effectively enhances extinction retention in individuals with PTSD. This will provide critical knowledge on the optimal, i.e. most effective, tDCS timing protocol to enhance extinction memory fundamental to successful exposure-based treatment. Results of the proposed research will directly inform further development of clinical trials aimed to test the application of tDCS to enhance exposure-based therapeutic interventions for PTSD. The current COBRE proposal will use a well-established fear-conditioning paradigm to systematically test how tDCS timing in relation to extinction learning affects physiological arousal (skin conductance responses) and associated neural responses using neuroimaging at time of extinction retention.